We reviewed functional imaging and postmortem data to conclude that brain failure in Alzheimer disease occurs in two stages. The first stage is associated with reduced synaptic efficacy and reduced glucose metabolism, and is potentially reversible. The second stage, in moderate-severe dementia, is associated with neurofibrillary tangle formation, cell death and synaptic dropout, and is irreversible. The brain can be almost normally activated in the first but not the second stage. (Rapoport 2005a, b).